On the basis of previous work done on the kinetics of repression of the histidine operon in Salmonella typhimurium, we suggested that the first enzyme for histidine biosynthesis plays a previously unrecognized role in control of the histidine operon. A prediction of this hypothesis is that certain mutations in the first structural gene (G gene) of the operon would lead to alterations in the structure of the first enzyme which affect regulation of the histidine operon. An episome bearing the histidine operon containing a mutation to feedback resistance has been isolated. The strain carrying this episome is not under repression control. This finding supports the hypothesis that the G enzyme plays a direct role in repression of the histidine operon. By transferring the episome into various strains, we have been able to study the dominance of the loss of repression control in this mutant. The regulatory mutation in the his G gene is trans recessive, i.e., if the episome is carried in a strain which has an unaltered his G gene on the chromosome, regulation of operon expression by histidine is restored. In addition, the mutant episome has been transferred into strains which have his T and his W mutations. In these strains the effect of the his G mutation is epistatic to the his T and his W mutations. This provides additional evidence that there is a relationship between the role of the first enzyme for histidine biosynthesis and histidyl-tRNA in regulation of the histidine operon.